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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human papillomaviruses (HPVs) are small double-stranded DNA viruses that infect the cutaneous and mucosal epithelium. Infection by specific HPV types has been linked to the development of cervical carcinoma. HPV infects epithelial cells that undergo terminal differentiation and so encode multiple mechanisms to override the normal regulation of differentiation to produce progeny virions. Two viral proteins, E6 and E7, alter cell cycle control and are the main arbitrators of HPV-induced oncogenesis. Recent data suggest that E6 and E7 also play a major role in the inhibition of the host cell innate immune response to HPV. The E1 and E2 proteins, in combination with various cellular factors, mediate viral replication. In addition, E2 has been implicated in both viral and cellular transcriptional control. Despite decades of research, the function of other viral proteins still remains unclear. While prophylactic vaccines to block genital HPV infection will soon be available, the widespread nature of HPV infection requires greater understanding of both the HPV life cycle as well as the mechanisms underlying HPV-induced carcinogenesis.
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PMID:Human papillomaviruses: basic mechanisms of pathogenesis and oncogenicity. 1628 4

Infection with CagA-positive Helicobacter pylori is associated with the development of gastric adenocarcinoma. The CagA gene product CagA is injected directly from the bacterium into the bacterium-attached gastric epithelial cells via the type-IV secretion system. Upon membrane localization and subsequent tyrosine phosphorylation by Src family kinases, CagA functions as a scaffolding adaptor and interacts with a number of host proteins that regulate cell growth, cell motility and cell polarity in both CagA phosphorylation-dependent and phosphorylation-independent manners. Of special interest is the interaction of CagA with the SHP-2 tyrosine phosphatase, gain-of-function mutations that of which have recently been found in a variety of human malignancies. The CagA-SHP-2 interaction is entirely dependent on CagA tyrosine phosphorylation and, through the complex formation, SHP-2 is catalytically activated and induces morphological transformation with elevated cell motility. Intriguingly, structural diversity of the tyrosine phosphorylation sites of CagA accounts for the differential activity of individual CagA to bind and activate SHP-2. Deregulation of SHP-2 and other intracellular signaling molecules by H. pylori CagA may predispose cells to accumulate multiple genetic and epigenetic changes involved in gastric carcinogenesis. Furthermore, the differential potential of individual CagA to disturb cellular functions indicates that H. pylori strains carrying biologically more active CagA are more virulent than those with less active CagA and are more closely associated with gastric carcinoma.
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PMID:Helicobacter pylori CagA: a new paradigm for bacterial carcinogenesis. 1636 2

Cervical cancer is one of the leading causes of cancer morbidity and mortality in women worldwide. More than 98% of cases are related to a human papillomavirus (HPV) infection. Infection with specific subtypes of HPV has been strongly implicated in cervical carcinogenesis. The identification and functional verification of host proteins associated with HPV E6 and E7 oncoproteins may provide useful information for understanding cervical carcinogenesis and the development of cervical cancer-specific markers. In addition, proteomic profiling of altered proteins by anticancer drugs on cervical cancer cells may contribute to providing the fundamental resources for investigation of disease-specific target proteins, elucidation of the novel mechanisms of action and development of new drugs. The advent of proteomics has provided the hope of discovering novel biological markers for use in the screening, early diagnosis and prediction of response to therapy. This review describes the studies where profiles of protein expression in cervical cancer have been generated.
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PMID:Role of proteomics in translational research in cervical cancer. 1644 48

Infection with high-risk human papillomavirus (HPV) has been implicated in the pathogenesis of esophageal squamous cell carcinoma, and up-regulation of telomerase in esophageal adenocarcinoma. We immortalized normal esophageal epithelial cells by over-expression of the HPV16 E6/E7 and human telomerase reverse transcriptase (hTERT) genes. HPV16 E6/E7-induced immortalization was accompanied by reduced RB and p53, but increased p16 and p21, protein expression. hTERT-immortalized cells had unaffected RB and p53, but significantly decreased p16 and p21, protein expression. Aurora-A protein was also up-regulated in E6E7 immortalized cells, and to a less extent in hTERT immortalized cells. Fluorescence in situ hybridization showed that the Aurora-A gene locus was amplified in E6E7 immortalized cells, which might account in part for the Aurora-A over-expression. These molecular changes led to an abrogation of the G2 checkpoint. E6E7 and hTERT immortalized esophageal cells recapitulated many of the molecular changes observed in esophageal carcinomas, where RB and p53 are frequently down-regulated. However, down-regulation of p16 and p21 occurred frequently in esophageal cancer, owing to aberrant gene promoter methylation. We showed in the immortalized cells that aberrant methylation had not yet set in, suggesting that promoter methylation might not be necessary for cellular immortalization. In addition to supporting the role of HPV and telomerase in esophageal carcinogenesis, our cell lines may also be useful in vitro models for further studies of esophageal carcinogenesis.
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PMID:Papillomavirus type 16 E6/E7 and human telomerase reverse transcriptase in esophageal cell immortalization and early transformation. 1648 74

Infection with cagA-positive Helicobacter pylori (H. pylori) is associated with the development of gastric adenocarcinoma. The cagA gene product CagA is delivered from the bacterium into the cytoplasm of the bacterium-attached gastric epithelial cell via the type-IV secretion system. Upon membrane localization and subsequent tyrosine phosphorylation by Src family kinases, translocated CagA functions as a scaffolding adaptor that interacts with a number of host proteins involved in cell signaling in both tyrosine phosphorylation-dependent and -independent manners. Of special interest is the interaction of CagA with the SHP-2 tyrosine phosphatase, of which gain-of-function mutations have recently been found in human malignancies. Through the complex formation, SHP-2 is catalytically activated and induces morphological transformation that is associated with increased cell motility. In addition to the perturbation of intracellular signaling, CagA disrupts the apical junctional complex that regulates the cell-cell contact and maintains the integrity of the epithelial structure. These CagA activities may collectively cause cellular dysfunctions that promote accumulation of multiple genetic changes involved in malignant transformation. Further elucidation of host cell signaling targeted by CagA should provide a new paradigm for 'bacterial carcinogenesis' and also give insights into general understanding of inflammation-mediated cancers. Clinically, detailed studies on the relationship between structural diversity and degree of pathogenic activity of CagA should make it possible to identify a high-risk group for gastric carcinoma among H. pylori-infected populations through cagA genotyping.
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PMID:Helicobacter pylori CagA -- a bacterial intruder conspiring gastric carcinogenesis. 1655 68

Infection and chronic inflammation are proposed to contribute to carcinogenesis through inflammation-related mechanisms. Infection with hepatitis C virus, Helicobacter pylori and the liver fluke, Opisthorchis viverrini (OV), are important risk factors for hepatocellular carcinoma (HCC), gastric cancer and cholangiocarcinoma, respectively. Inflammatory bowel diseases (IBDs) and oral diseases, such as oral lichen planus (OLP) and leukoplakia, are associated with colon carcinogenesis and oral squamous cell carcinoma (OSCC), respectively. We performed a double immunofluorescence labeling study and found that nitrative and oxidative DNA lesion products, 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), were formed and inducible nitric oxide synthase (iNOS) was expressed in epithelial cells and inflammatory cells at the site of carcinogenesis in humans and animal models. Antibacterial, antiviral and antiparasitic drugs dramatically diminished the formation of these DNA lesion markers and iNOS expression. These results suggest that oxidative and nitrative DNA damage occurs at the sites of carcinogenesis, regardless of etiology. Therefore, it is considered that excessive amounts of reactive nitrogen species produced via iNOS during chronic inflammation may play a key role in carcinogenesis by causing DNA damage. On the basis of our results, we propose that 8-nitroguanine is a promising biomarker to evaluate the potential risk of inflammation-mediated carcinogenesis.
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PMID:Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis. 1660 33

Mortality from bladder cancer has shown downward trends over the last 2 decades in several western European countries (albeit 10-15 years later than similar trends in the US), but is still increasing in some eastern European countries. Tobacco smoking and occupational exposure to aromatic amines are the two major established environmental risk factors for bladder cancer. Controlling exposure to these factors has been an important contributor to the reduction in bladder cancer mortality, particularly among men. Diet could influence bladder carcinogenesis, as many compounds contained in foods--and their metabolites--are excreted through the urinary tract. Fruit and vegetable consumption was inversely related with bladder cancer in many studies, but no consistent association has emerged between intake of related micronutrients and reduced risk of bladder cancer. Other widely investigated lifestyle habits are probably not associated with risk of developing bladder cancer (e.g. coffee consumption, artificial sweetener use, hair dyes) or are difficult to assess (e.g. fluid intake). Infections and stones in the urinary tract might cause chronic irritation of the bladder epithelium, and thus increase bladder cancer risk. First-degree relatives of bladder cancer patients have a 50-100% increased relative risk of developing the disease, a risk that could be even higher when the proband is diagnosed at an early age.
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PMID:Mechanisms of disease: The epidemiology of bladder cancer. 1676 21

Gastric carcinogenesis is a multistep process progressing from chronic gastritis, through glandular atrophy (GA), intestinal metaplasia (IM) and dysplasia. Infection of the stomach with H. pylori increases the risk of developing gastric cancer. Few studies have examined the degree to which Hp-induced changes occur in specific populations. In the present study, we examined the association between Hp infection and histological changes in the gastric mucosa of patients at two inner-city hospitals in New York. Patients enrolled in this study were undergoing endoscopy for gastrointestinal complaints. One antral biopsy was taken for detecting and genotyping Hp by PCR. Additional biopsies were taken from the antrum and fundic region for histological analysis and were scored with respect to acute and chronic inflammation, GA, IM and Hp infestation according to the Sydney classification. Hp strains infecting these patients were genotyped with respect to the expression of Hp virulence factors including VacA, CagA, and BabA2. Samples were collected from 126 patients at Kings County Hospital in Brooklyn and St. John's Episcopal Hospital in Queens. Hp infection rates were highest in Blacks (41.6%) and Hispanics (29.4%) and lowest in Caucasians (18.8%). Scores for acute and chronic inflammation and IM were higher in Hp-infected individuals in both the antrum and fundic regions, whereas Hp infection did not affect the incidence or intensity of GA. In Hp-infected individuals, the incidence of IM was greater in the antrum (Hp-infected 37.8% vs. non-infected 9.2%, p < 0.05) and fundic region (Hp-infected 15.1% vs. noninfected 1.8%, p < 0.05). Genotyping of the Hp strains infecting these patients revealed that the predominant VacA allele was s1 bm 1 and that the CagA gene was present in 69.8% of Hp-infected samples. Interestingly, the BabA2 gene was detected in only four samples (9.3%). The incidence of IM in the antrum was higher in CagA + samples when compared with CagA- samples (52.2% vs. 15.4%, respectively). Our findings indicate that the virulent Hp strain infecting minority patients treated at inner-city hospitals in New York City is associated with a high incidence of IM and that these patients may be at greater risk for developing gastric cancer than the general population.
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PMID:Helicobacter pylori infection is associated with a high incidence of intestinal metaplasia in the gastric mucosa of patients at inner-city hospitals in New York. 1694 98

The interplay between human papillomavirus, notably type 16, and HIV in cervical carcinogenesis leads to persistent infection and cervical neoplasia by destruction of the afferent arm (Langerhans cells) of the host immune system. The joint effect takes place at the early stages of squamous intraepithelial lesions and has severe consequences if left untreated. The recent increase of cervical cancer mortality in young women in developed countries may well be a result of the HIV epidemic. Infection with Chlamydia trachomatis is associated with cervical squamous cell carcinoma but not with cervical adenocarcinoma, and the association remains after adjusting for human papillomavirus 16. Joint effects of C. trachomatis and the human papillomaviruses have not been studied at the population level but indirect evidence from epidemiological studies suggests that the interaction might be different (synergistic versus antagonistic) at different stages (cervical intraepithelial neoplasia versus invasive cervical cancer) of cervical carcino-genesis. Concomitant exposure to human papillomaviruses 6 or 11 and human papillomavirus type 16 has not been shown to result in excess risk of cervical squamous cell carcinoma. This antagonistic joint effect was also discovered between human papillomavirus types 18 and 16, as well as 33 and 16. Herpes simplex virus type 2 antibodies are associated with a modest risk of cervical cancer, which is not surprising since the presence of herpes simplex virus antibodies reflects risk-taking sexual behaviour. However, no excess risk remains after adjustment for human papillomavirus type 16, and no interaction between these two viruses has been found in epidemiological studies. Evidence of interaction between human papillomavirus type 16 and the other members of the herpesvirus family is still at an experimental level and difficult to judge. Little progress has been made in the most promising experimental association between the oncogenic human papillomaviruses and adeno-associated viruses. In addition to the well established interaction between human papillomaviruses and HIV, intriguing interactions are emerging between the human papillomaviruses and C. trachomatis, as well as between the different human papillomavirus types.
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PMID:Interactions between human papillomavirus and other sexually transmitted agents in the etiology of cervical cancer. 1703 63

We have adapted the avian leukosis virus RCAS (replication-competent avian sarcoma-leukosis virus LTR splice acceptor)-mediated somatic gene transfer technique to introduce oncogenes into mammary cells in mice transgenic for the avian subgroup A receptor gene, tva, under control of the mouse mammary tumor virus (MMTV) promoter. Intraductal instillation of an RCAS vector carrying the polyoma middle T antigen (PyMT) gene (RCAS-PyMT) induced multiple, oligoclonal tumors within 3 weeks in infected mammary glands of MMTV-tva transgenic mice. The rapid appearance of these tumors from a relatively small pool of infected cells (estimated to be approximately 2 x 10(3) cells per gland by infection with RCAS carrying a GFP gene; RCAS-GFP) was accompanied by a high fraction of cells positive for Ki67, Cyclin D1, and c-Myc, implying strong proliferation competence. Furthermore, the tumors displayed greater cellular heterogeneity than did tumors arising in MMTV-PyMT mice, suggesting that RCAS-PyMT transforms a relatively immature cell type. Infection of mice transgenic for both MMTV-Wnt-1 and MMTV-tva with RCAS virus carrying an activated Neu oncogene dramatically enhanced tumor formation over what is observed in uninfected bitransgenic animals. We conclude that infection of mammary glands with retrovirus vectors is an efficient means to screen candidate oncogenes for their capacity to initiate or promote mammary carcinogenesis in the mouse.
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PMID:Introduction of oncogenes into mammary glands in vivo with an avian retroviral vector initiates and promotes carcinogenesis in mouse models. 1709 Jun 66


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